The complement system is composed of nearly 50 individual proteins that functions as a part of the innate immune system providing the initial phase of host defense, opsonization of foreign material, and tissue homeostasis. (Ricklin D., 2010, Complement: a Key system for immune surveillance and homeostasis. Nature: Immunology, 785-795) The complement system is found in all multicellular organism and phylogenetically predates the formation of the adaptive immune system (Zarkadis I. K., 2001 Phylogenetic aspects of the complement system. Development and Comparative Immunology, 745-762.).
Activation of the complement system occurs along three primary pathways: classical, lectin and alternative pathways. During the activation process sequential protein-protein interactions and proteolytic activity leads the generation of the C3 and C5 convertases. These convertases are responsible for producing complement activation split products that represent the effector molecules of the complement cascade important for opsonization, generation of anaphylatoxins, and the formation of the membrane attack complex (MAC). The latter of these is essential for the lytic activity of the complement cascade (Ricklin D., 2010). Under normal conditions activation of the complement cascades provides defense against pathogenic bacterial, as well as clearance of diseased and injured tissue. Normally, the formation of MAC does not affect surrounding tissue due to the presence of cell surface and soluble regulatory components which include CFH, CFH related proteins, C4BP, CD46, CD55, CD59, and complement factor I (CFI). However, when excess activation occurs or when there is a failure to produce complement negative regulatory components, both acute and chronic disease states are induced. Examples in which uncontrolled complement activation is recognized as causative to human pathologies include: Glomerulonephritis, Systemic Lupus Erythematosus, Paroxysomal Nocturnal Hemoglobinuria, Alzheimer's, Hereditary Angioedmea, Myasthenia Gravis and Age-related Macular Degeneration (AMD) (Ricklin & Lambris, 2013, Complement in Immune and inflammatory Disorders: Pathological Mechanisms. Journal of Immunology, 3831-3838).
Complement factor B is a protein that circulates in the blood as a single chain polypeptide. Upon activation of the alternative pathway, Factor B (nearly 750 aa) is cleaved by complement Factor D yielding two polypeptides, the smaller, non-catalytic chain Ba (about 230 aa; comprising three complement control protein (CCP) domains) and the larger, catalytic subunit Bb (about 510 aa; comprising a protein interaction domain and a serine protease domain). Factor Bb is a serine protease that associates with C3b to form the alternative pathway's C3 convertase as well as a second protease, C5 convertase, which cleaves the C5 protein into C5a and C5b. Cleavage product C5b initiates the membrane attack pathway, which results in the membrane attack complex (MAC). The MAC is a transmembrane channel, which results in osmotic lysis of the target pathogen. Thus, cleavage of Factor B and production of Factor Bb aids in the complement process.
Factor B is a tightly regulated, highly specific serine protease. In its activated form, it catalyzes the central amplification step of complement activation to initiate inflammatory responses, cell lysis, phagocytosis and B-cell stimulation (Carroll et al., Nat. Immunol. 5:981-986 (2004)). Factor B is activated through an assembly process: it binds surface-bound C3b, or its fluid-phase counterpart C3 (H2O), after which it is cleaved by factor B into fragments Ba (residues 1-234; Factor Ba, Fragment Ba, Complement Factor Ba) and Bb (residues 235-739; Factor Bb, Fragment Bb, Complement Factor Bb). Fragment Ba dissociates from the complex, leaving behind the alternative pathway C3 convertase complex C3b-Bb, which cleaves C3 into C3a and C3b.
Age-related Macular Degeneration (AMD) is the leading cause of blindness in the elderly in the developed nations. In the US population alone the prevalence of advanced forms of AMD are associated with vision loss occurs in nearly 2 million individuals. Another 7 million individuals with intermediate AMD are at a high risk for development of advanced forms of AMD. Inclusion of the European population nearly doubles the number of impacted individuals. AMD is characterized by a progressive loss of vision attributable to a parainflammatory process causing the progressive degeneration of the neuroretina, and support tissues which include the retinal pigmented epithelium (RPE) and choriocapillaris. The majority of clinically significant vision loss occurs when the neurodegenerative changes impact the region of central vision within a highly specialized region of the eye, responsible for fine visual acuity, the macula. The disease has a tremendous impact on the physical and mental health of the individual due to vision loss and increased dependence on family members to perform everyday tasks.
The deregulation of the complement system is highly correlated with the development of AMD. First, genetic mutations in complement genes alter a person's risk of developing AMD. In addition, AMD-related inflammation is associated deregulation of complement activity as indicated by elevation of complement activation products in systemic circulation and in AMD tissues by histopathological analysis. New discoveries, have highlighted the the potential pathological impact of the membrane attack complex in disease occurrence (Whitmore S, et al. 2014, Complement activation and choriocapillaris loss in early AMD: Implications for pathphysiology and therapy. Progress in Retinal and Eye Research, Dec. 5, 2014 EPub ahead of print).
The present invention provides anti-Factor Bb antibodies for the prevention and treatment of complement associated diseases, AMD, and other complement-associated eye conditions.